Tumor-derived prostaglandin E2 promotes p50 NF-kB-dependent differentiation of monocytic MDSCs

Myeloid-derived suppressor cells (MDSC) include immature monocytic (M-MDSC) and granulocytic (PMN-MDSC) cells that share the ability to suppress adaptive immunity and to hinder the effectiveness of anticancer treatments. Of note, in response to IFNg, M-MDSCs release the tumor-promoting and immunosuppressive molecule nitric oxide (NO), whereas macrophages largely express antitumor properties. Investigating these opposing activities, we found that tumor-derived prostaglandin E2 (PGE2) induces nuclear accumulation of p50 NF-kB in M-MDSCs, diverting their response to IFNg toward NO-mediated immunosuppression and reducing TNFa expression. At the genome level, p50 NF-kB promoted binding of STAT1 to regulatory regions of selected IFNg-dependent genes, including inducible nitric oxide synthase (Nos2). In agreement, ablation of p50 as well as pharmacologic inhibition of either the PGE2 receptor EP2 or NO production reprogrammed M-MDSCs toward a NOS2^low/TNFa^high phenotype, restoring the in vivo antitumor activity of IFNg. Our results indicate that inhibition of the PGE2/p50/NO axis prevents MDSC-suppressive functions and restores the efficacy of anticancer immunotherapy.